TWI491392B - Methods of reducing small, dense ldl particles - Google Patents

Description

Method for reducing small, dense low density lipoprotein (LDL) particles

This patent application claims priority to U.S. Provisional Patent Application Serial No. 61/106,48, filed on Jan. 17, 2008, which is hereby incorporated by reference.

A causal relationship between increased levels of low-density lipoprotein (LDL) cholesterol and risk of coronary heart disease (CHD) has been recognized in the industry (Kanel, WB et al., Ann Intern Med, 74: 1-12 (1971); 4S Trial 1994; Shepherd 1995; WOSCOPS Trial 1998; Sacks 1998; Pedersen 1998). However, it has long been known that many individuals with high LDL cholesterol never have coronary artery disease (CAD), while a significant proportion of individuals with early-onset CAD have normal LDL cholesterol levels (Kanel, WB, Am J Cardiol). , 76: 69C-77C (1995)).

Another atherogenic risk factor identified in 1982 is LDL particle size and density, which can be used to define specific LDL subclasses of individual individuals (Krauss, RM and Burke, DJ, J Lipid Res, 23:97-104 ( 1982)). In the first population-based case-control study to explore this hypothesis, a large number of dense small LDL particles (defining the LDL B pattern) increased the risk of myocardial infarction (MI) by a factor of three (Austin, MA, etc.) Man, JAMA, 260: 1917-21 (1988)). Later, a large number of case-control studies found that patients with early-onset CAD had smaller LDL particle sizes than controls (Campos, H. et al., Arterioscler Thromb, 12: 187-95 (1992)). Or LDL particles that are smaller and denser than the control (Coresh, J. et al, J Lipid Res, 34: 1687-97 (1993)). The concentration of dense small LDL in men with CAD confirmed by angiography was significantly higher than that of men without CAD, with an odds ratio of 4.5 (p<0.01); men with previous MI compared with healthy controls The odds ratio is even higher (6.9, p < 0.001) (Griffen, BA. et al., Atherosclerosis, 106: 241-53 (1994)).

The important findings from these case-control studies, namely the relationship between LDL B-mode (large numbers of dense small LDL) and increased risk of CAD and MI, have recently been used in several large prospective studies using embedded pathology control design. It has been confirmed that these studies include the Physicians Health Study (Stampfer, MJ et al., JAMA, 276: 882-8 (1996)), and the Stanford Five City Project (Gardner, CD). Et al, JAMA, 276:875-81 (1996)), and Quebec Cardiovascular Study (Lamarche, B. et al., Circulation, 95: 69-75 (1997)). A large number of dense small LDLs have a strong correlation with CAD and are independent of traditional coronary risk factors (Austin, MA et al, JAMA, 260: 1917-21 (1988); Austin, MA et al, Curr Opin Lipidol, 5:395 -403 (1994); Stampfer, MJ et al, JAMA, 276: 882-8 (1996); Bjornheden, T. et al, Atherosclerosis, 123: 43-56 (1996); Lamarche, B. et al., Circulation, 95: 69-75 (1997); Koba, S. et al., Am Heart J, 144: 1026-35 (2002); Moon, JY et al., Cardiology, 108: 282-289 (2007)). It has also been demonstrated that dense small LDL is a major risk factor for early-onset CAD in women, regardless of age, menopausal status, smoking, hypertension, diabetes, and LDL cholesterol levels (Kamigaki, AS et al, Am J Epidemiol, 153 (10) :939-45 (2001)). Smaller LDL particle sizes are also associated with the risk of developing atherosclerosis, as assessed by coronary angiography (Swinkels, DW et al, Atherosclerosis, 77: 59-67 (1989); Tornvall, P. et al. Human, Atherosclerosis, 90: 67-80 (1991); Tornvall, P. et al, Circulation, 88: 2180-9 (1993); Rajman, I. et al, Atherosclerosis, 125: 231-242 (1996)). Rajman, I. et al., Br J Pharmacol, 48: 125-33 (1999)). It has been demonstrated in the industry that treatment to reduce the amount of dense small LDL and/or increase HDL cholesterol reduces the risk of cardiac events (Coronary Drug Project Research Group, Clofibrate and niacin in coronary heart disease, JAMA, 231:360-81 (1975); Marais, AD, Curr Opin Lipidol, 11: 597-602 (2000); Otvos, JD et al, Atherosclerosis, 160: 41-8 (2002)).

The atherogenic nature of dense small LDL particles appears to be caused by a variety of underlying mechanisms including: increased oxidative sensitivity; increased vascular permeability; affinity for LDL receptors (and thus clearance by LDL receptors) Reduced; conformational change of apo B in dense small particles; a clear correlation between this LDL reduction and insulin resistance/metabolic syndrome; and the association of this LDL pattern with hypertriglyceridemia and low HDL cholesterol (Austin , MA and Edwards, KL, Curr Opin Lipid, 7(3): 167-71 (1996)). In addition, the fraction of dense small LDL particles is stronger than that of lipoprotein (a) [Lp(a)] (Moon, JY et al., Cardiology, 108: 282-289 (2007)), and known cardiovascular risk factors. Correlation (Dahlen, GH et al, Circulation, 74: 758-65 (1986); Terres, W. et al, Circulation, 91: 948-50 (1995); Hahnmann, HW et al, Atherosclerosis, 144:221- 8 (1999); Uusimaa, P. et al., Heart Vessels, 16: 37-41 (2002)). Lp(a) is also associated with the content of oxidized phospholipids, which may play an important role in the pathophysiology of atherosclerosis (Tsimikas, S. et al., J Am Cell Cardiol, 41: 360-70 (2003). )).

A few currently available drugs can significantly increase the size of LDL particles and reduce the density of LDL particles. One of the most widely used lipid-lowering agents, statins, tends to reduce LDL particle size and increase density, possibly due to up-regulation of LDL receptors with higher affinity for larger low-density LDL particles. (Rajman, I. et al., Br J Pharmacol, 48: 125-33 (1999)). However, the three classes of drugs appear to reduce the atherogenic dense small LDL particles. Nicotinic acid clearly reduces dense small LDL, which is mainly caused by lowering triglyceride content, and the LDL particle size of individuals with normal triglyceride content is only moderately reduced (Griffen, BA et al., Eur J Clin Invest, 22: 383-90 (1992); Superko, HR and Krauss, RM, Atherosclerosis, 95: 69-76 (1992)). Similarly, fibrates reduce the content of dense small LDL particles in patients with mixed hyperlipidemia (Tsai, MY et al, Atherosclerosis, 95: 35-42 (1992); Bruckert, E. Et al, Atherosclerosis, 100: 91-102 (1993); Yuan, J. et al, Atherosclerosis, 110: 1-11 (1994)), and for hypercholesterolemia but with normal triglyceride content This is not the case (Yuan, J. et al., Atherosclerosis, 110: 1-11 (1994)). Finally, thiazolidinedione (TZD) has consistently been shown to increase LDL particle size and reduce LDL particle density, which appears to be associated with improved insulin sensitivity but not associated with hypertriglyceridemia (Tack, CJJ et al. Diabetes care, 21: 796-9 (1998); Freed, MI et al, Am J Cardiol, 90: 947-52 (2002); Winkler, K. et al., Diabetes Care, 26: 2588-94 (2003); Shadid, S. et al., Atherosclerosis, 188: 370-6 (2006)).

The present invention provides a method of reducing the amount of dense small LDL particles of a human having an LDL particle size I or B mode. In certain embodiments, the method comprises administering to a human a therapeutically effective amount of a compound of Formula I, or a salt, prodrug or isomer thereof, wherein the post-administration LDL particle size mode: from I mode to A mode; Or change from B mode to I or A mode.

In certain embodiments, the human has a lower level of LDL-III particles after the step of administering than before the step of administering. In certain embodiments, the human has a lower level of LDL-IV particles after the step of administering than before the step of administering.

In certain embodiments, the compound is

Or a salt, prodrug or isomer thereof.

In certain embodiments, the compound is

Or its salt or prodrug.

In certain embodiments, the human has an LDL particle size A mode after 10 days of administration (eg, after 20 days, eg, 10-100, 10-1000 days). In certain embodiments, the human has an LDL particle size I pattern after 10 days (eg, after 20 days, eg, 10-100, 10-1000 days) after the administration step. In certain embodiments, the method further comprises measuring the LDL particle size of the human prior to the administering step. In certain embodiments, the method further comprises measuring the LDL particle size of the human after the administering step.

In certain embodiments, the human has an LDL particle size B mode prior to the step of administering. In certain embodiments, the human has an LDL particle size I mode prior to the step of administering.

In certain embodiments, a human has diabetes. In certain embodiments, the human has insulin resistance. In certain embodiments, the human does not have diabetes. In certain embodiments, the human has atherosclerosis. In certain embodiments, the human has metabolic syndrome. In certain embodiments, the human has a dyslipidemia. In certain embodiments, the human does not have atherosclerosis. In certain embodiments, the human does not have diabetes. In certain embodiments, the human is not suffering from insulin resistance. In certain embodiments, the human does not have metabolic syndrome. In certain embodiments, the human is not suffering from dyslipidemia.

In certain embodiments, the lipoprotein B-100 blood content is reduced by at least 5% or at least 10% or at least 15 after 10 days of administration (eg, after 20 days, eg, 10-100, 10-1000 days). % or at least 20%. In certain embodiments, the absorption of cholesterol is reduced by at least 5% or at least 10% or at least 15% or at least 20% after 10 days of administration (eg, after 20 days, eg, 10-100, 10-1000 days). . In certain embodiments, cholesterol synthesis is reduced by at least 5% or at least 10% or at least 15% or at least 20% after 10 days of administration (eg, after 20 days, eg, 10-100, 10-1000 days).

In certain embodiments, the LDL cholesterol blood content is reduced by at least 15% after 10 days of administration (eg, after 20 days, eg, 10-100, 10-1000 days). In certain embodiments, the triglyceride blood content is reduced by at least 20% after 10 days of administration (eg, after 20 days, eg, 10-100, 10-1000 days). In certain embodiments, the HDL cholesterol blood content is increased by at least 5% after 10 days of administration (eg, after 20 days, eg, 10-100, 10-1000 days).

The present invention also provides methods of reducing the triglyceride and LDL blood levels of humans having LDL particle size I or B patterns. In certain embodiments, the method comprises administering to a human a therapeutically effective amount of a compound of Formula I, or a salt, prodrug or isomer thereof, wherein the post-administration LDL particle size mode: from I mode to A mode; Or change from B mode to I or A mode.

In certain embodiments, the compound is

Or a salt, prodrug or isomer thereof.

In certain embodiments, the compound is

Or its salt or prodrug.

In certain embodiments, the method further comprises administering to the human a statin. In certain embodiments, the statin is atorvastatin.

The invention also provides methods of determining a candidate for treatment with a compound of formula I or a salt, prodrug or isomer thereof. In certain embodiments, the method comprises measuring an LDL peak particle size of the individual; and if the individual has an I or B mode LDL particle size pattern, administering the compound to the individual.

In certain embodiments, the individual has an I-mode LDL particle size mode and the compound is administered to the individual after the measuring step. In certain embodiments, the individual has a B-mode LDL particle size mode and the compound is administered to the individual after the measuring step.

The invention also provides a therapeutically effective amount of a compound of formula I, or a salt, prodrug or isomer thereof, for use in a human having an LDL particle size I or B mode, wherein the amount is sufficient to allow human LDL particle size patterns From I mode to A mode; or from B mode to I or A mode.

In certain embodiments, the compound is

Or a salt, prodrug or isomer thereof.

In certain embodiments, the compound is

Or its salt or prodrug.

In certain embodiments, the amount is sufficient such that the human has an LDL particle size A mode 10 days after the administration step. In certain embodiments, the human has an LDL particle size B mode prior to the step of administering. In certain embodiments, the human has an LDL particle size I mode prior to the step of administering.

In certain embodiments, the compound is for use in a human having diabetes. In certain embodiments, the compound is for use in a human having insulin resistance. In certain embodiments, the compound is for use in a human having atherosclerosis. In certain embodiments, the compound is for use in a human having metabolic syndrome. In certain embodiments, the compound is for use in a human having dyslipidemia.

In certain embodiments, the amount is sufficient to reduce the blood content of lipoprotein B-100 by at least 10% after 10 days of administration.

In certain embodiments, the amount is sufficient to reduce absorption of cholesterol by at least 5% after 10 days of administration.

In certain embodiments, the amount is sufficient to reduce cholesterol synthesis by at least 5% after 10 days of administration.

In certain embodiments, the amount is sufficient to reduce absorption of cholesterol by at least 10% after 10 days of administration.

In certain embodiments, the amount is sufficient to reduce cholesterol synthesis by at least 10% after 10 days of administration.

In certain embodiments, the amount is sufficient to reduce absorption of cholesterol by at least 20% after 10 days of administration.

In certain embodiments, the amount is sufficient to reduce cholesterol synthesis by at least 20% after 10 days of administration.

In certain embodiments, the amount is sufficient to reduce the blood content of LDL cholesterol by at least 15% after 10 days of the administration step.

In certain embodiments, the amount is sufficient to reduce the triglyceride blood content by at least 20% after 10 days of administration.

In certain embodiments, the amount is sufficient to increase the blood content of HDL cholesterol by at least 5% after 10 days of the administration step.

The invention also provides a method comprising:

a) testing human LDL particle size; and

b) if the human has an LDL particle size I or B mode, providing a therapeutically effective amount of a compound of formula I or a salt, prodrug or isomer thereof to the human, wherein the amount is sufficient to allow human LDL particle size mode from I The mode changes to A mode; or changes from B mode to I or A mode. The term "providing" as used in this context is not intended to mean administration, but encompasses the formulation of a drug for humans and/or the provision of a compound (eg, in the form of a pill) that humans may consume at the time or later.

In certain embodiments, the compound is

Or a salt, prodrug or isomer thereof.

In certain embodiments, the compound is

Or its salt or prodrug.

In certain embodiments, the method further comprises measuring the LDL particle size of the human after the providing step and after the human introduces the compound into the human body.

In certain embodiments, the human has an LDL particle size B mode prior to the providing step. In certain embodiments, the human has an LDL particle size I mode prior to the providing step.

In certain embodiments, a human has diabetes. In certain embodiments, the human has insulin resistance. In certain embodiments, the human does not have diabetes. In certain embodiments, the human has atherosclerosis. In certain embodiments, the human has metabolic syndrome. In certain embodiments, the human has a dyslipidemia.

definition

"LDL particle size" or "LDL particle size" refers to the diameter of LDL particles in blood. See, for example, Krauss, RM et al, J. Lipid. Res. 23:97-104 (1982); Shen, MMS et al, J. Lipid. Res. 22:235-244 (1981). A variety of methods for measuring the size of LDL particles have been known, including but not limited to gradient gel electrophoresis (GGE) and airborne ion transport (AIM). Particles can be classified according to their diameter. For example, LDL particles can be divided into four (I-IV), with I being the largest particle and having the smallest IV. Using the AIM measurement method, LDL-I corresponds to particles with a diameter of 21.99-23.80 nm, LDL-II corresponds to particles with a diameter of 21.10-21.99 nm, and LDL-III corresponds to particles with a diameter of 20.17-21.10 nm, and LDL -IV corresponds to particles having a diameter of 18.00-20.17 nm. See, for example, Berneis and Krauss, J. Lipid Res. 43: 1363-1379 (2002).

In many individuals, one size of LDL particles is predominant (ie, present in the highest amount) compared to other sizes of LDL particle systems. The size of the primary LDL particle can vary from individual to individual. Smaller particles are considered risk factors for certain diseases including, but not limited to, coronary artery disease (see, for example, Berneis and Krauss, J. Lipid Res. 43: 1363-1379 (2002)). Individuals with smaller major LDL particles (less than 25.75 nm, as measured by GGE) have a "B mode" with a poor diagnosis. Individuals with larger major LDL particles (greater than 26.34 nm, as measured by GGE) have "A mode". Individuals with a primary LDL particle size between A mode and B mode (ie, a primary LDL particle size of 25.75-26.34 nm, as measured by GGE) are said to have an "I mode."

The term "therapeutically effective amount" means the amount of a target compound that will cause a tissue, system, animal or human to elicit a biological or medical response that a researcher, veterinarian, physician or other clinician is seeking. A therapeutically effective amount comprises an amount of a compound sufficient to effect such treatment for the disease when administered to a mammal for the treatment of a disease. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

The term "insulin resistance" can generally be defined as a disorder of glucose metabolism. More specifically, insulin resistance can be defined as the ability of insulin to exert its biological effects over a wide range of concentrations compared to the expected biological effects (see, for example, Reaven, GM, J. Basic & Clin. Phys. & Pharm). (1998) 9:387-406 and Flier, J. Ann Rev. Med. (1983) 34: 145-60). People with insulin resistance have reduced ability to properly metabolize glucose. The manifestations of insulin resistance include insufficient insulin activation in the intramuscular glucose uptake, oxidation and storage, and insufficient insulin inhibition in lipolysis in the adipose tissue and glucose production and secretion in the liver. Insulin resistance can cause or contribute to polycystic ovary syndrome, glucose intolerance (IGT), gestational diabetes, hypertension, obesity, hypertriglyceridemia, atherosclerosis, and a variety of other conditions. Finally, insulin-resistant individuals can develop to the point of reaching a diabetic state. Insulin resistance and glucose intolerance, increased plasma triglyceride concentration and decreased high-density lipoprotein cholesterol concentration, hypertension, hyperuricemia, less dense low-density lipoprotein particles, and higher circulating levels The combination of plasminogen activator inhibitor-1 is called "symptom X" (see, for example, Reaven, GM, Physiol. Rev. (1995) 75: 473-486), also known as "metabolic syndrome". "."

"Insulin sensitivity" refers to the ability of a cell or tissue to respond to insulin. Individuals with insulin resistance have lower insulin sensitivity than healthy wasting individuals. The response includes, for example, glucose uptake by the cells or tissue in response to insulin stimulation. Sensitivity can be measured at the organism, tissue or cell level. For example, blood or urine glucose levels after glucose tolerance testing are indicative of insulin sensitivity. Other methods of measuring insulin sensitivity include, for example, measuring glucose uptake (see, for example, Garcia de Herreros, A. and Birnbaum, MJJ Biol. Chem. 264, 1999 4-19999 (1989); Klip, A., Li. , G. and Logan, WJ Am. J. Physiol. 247, E291-296 (1984)), measuring the infusion rate (GINF) of glucose into tissues (eg skeletal muscle) (see, for example, Ludvik et al., J) Clin. Invest. 100:2354 (1997); Frias et al., Diabetes Care 23:64, (2000)) and measuring the sensitivity of GLUT4 translocation to insulin response.

The term "diabetes mellitus or diabete" means a disease or condition that is generally characterized by the production and utilization of metabolic defects in glucose that result in an inability to maintain an appropriate blood glucose level in the body. The result of these defects is an increase in blood sugar, which is called "hyperglycemia." The two main forms of diabetes are type 1 diabetes and type 2 diabetes. As mentioned above, type 1 diabetes is usually the result of an absolute lack of insulin, a hormone that regulates glucose utilization. Type 2 diabetes often occurs in the presence of normal, or even high levels of insulin and can result from the tissue's lack of ability to respond appropriately to insulin. Most patients with type 2 diabetes have insulin resistance and are relatively deficient in insulin because insulin secretion does not compensate for the resistance of peripheral tissues to insulin resistance. In addition, many but not all patients with type 2 diabetes are obese. Other types of glucose homeostasis disorders include glucose intolerance, which is intermediate in the intermediate metabolic phase between normal glucose homeostasis and diabetes; and gestational diabetes, a woman who has not previously had a history of type 1 or type 2 diabetes. Glucose tolerance during pregnancy.

The term "obesity" and "obesity" means according to the World Health Organization body mass index (BMI) greater than 27.8 kg male / female m ² and greater than 27.3 kg / m ² (BMI equals weight (kg) / height (m ^2). Obesity The disease is associated with a variety of medical conditions including diabetes and hyperlipidemia. Obesity is also a well-known risk factor for developing type 2 diabetes (see, for example, Barrett-Conner, E., Epidemol. Rev. (1989) 11: 172-181; and Knowler et al., Am. J. Clin. Nutr. (1991) 53: 1543-1551).

Unless otherwise indicated, as used herein and whether used alone or as part of the substituent group, "alkyl" and "alkoxy" includes a straight chain having from 1 to 8 carbon atoms and branched chain C ₁ e.g. _-6 , C _1-4 , C _3-8 , C _2-5 , or any other range, and unless otherwise stated, both substituted and unsubstituted moieties are included. For example, a C _1-6 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl, 3-( 2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. The alkoxy group is formed from the aforementioned linear or branched alkyl group. "Alkyl" and "alkoxy" include unsubstituted moieties or moieties substituted with one or more substituents, for example having from 1 to 5, 1 to 3, or 2 to 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chloro, fluoro) or different (substituted with chlorobenzyl or aminomethyl). Examples of substituted alkyl groups include haloalkyl groups (e.g., fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, trifluoromethyl, and 3-iodocyclopentyl), hydroxyalkanes Base (eg hydroxymethyl, hydroxyethyl, 2-hydroxypropyl), aminoalkyl (eg aminomethyl, 2-aminoethyl, 3-aminopropyl and 2-aminopropyl) , alkoxyalkyl, nitroalkyl, alkylalkyl, cyanoalkyl, phenylalkyl, heteroarylalkyl, heterocyclylalkyl, phenoxyalkyl, heteroaryloxy An alkyl group (e.g., 2-pyridyloxyalkyl), a heterocyclyloxy-alkyl group (e.g., 2-tetrahydropyranyloxy-alkyl), a sulfanylalkyl group (e.g., MeS-alkyl), Thiophenylalkyl (e.g., phS-alkyl), carboxyalkyl, and the like. The di(C _1-3 alkyl)amine group contains independently selected alkyl groups to form, for example, methylpropylamino and isopropylmethylamino groups, and further the dialkylamino group has two identical alkyl groups. A group such as a dimethylamino group or a diethylamino group.

The term "alkenyl" embraces straight-chain and branched hydrocarbon groups as defined above, optionally having at least one carbon-carbon double bond (sp ₂ ). Alkenyl includes vinyl (ethenyl or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl , but-2-enyl, butadienyl, pentenyl, hexa-2,4-dienyl and the like. A hydrocarbon group having a mixed bond of a double bond and a triple bond (for example, 2-penten-4-ynyl) is classified herein as an alkynyl group. Alkenyl groups contain a cycloalkenyl group. The cis and trans or (E) and (Z) forms are included in the present invention. "Alkenyl" may be substituted by one or more substituents including, but not limited to, cyanoalkenyl and thioalkenyl.

The term "alkynyl" embraces straight-chain and branched hydrocarbon radicals as defined above, optionally having at least one carbon-carbon triple bond (sp). An alkynyl group includes an ethynyl group, a propynyl group, a butynyl group, and a pentynyl group. A hydrocarbon group having a mixed bond of a double bond and a triple bond (for example, 2-penten-4-ynyl) is classified herein as an alkynyl group. Alkynyl does not contain a cycloalkynyl group.

The term "Ac" as used herein, alone or as part of a substituent, means ethyl hydrazino (CH. ₃ CO-).

The term "halogen" or "halo" shall contain iodine, bromine, chlorine and fluorine.

The term "aryl" or "Ar" as used herein refers to an unsubstituted or substituted aromatic hydrocarbon ring system, such as phenyl and naphthyl. When an aryl group (Ar or aryl) is substituted, it may have 1 to 3 substituents independently selected from C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, fluorinated C ₁ -C ₈ alkyl (eg, trifluoromethyl), fluorinated C _1- C ₈ alkoxy (e.g., trifluoromethoxy), halogen, cyano, C _1- C ₈ alkylcarbonyl (e.g., ethenyl), carboxyl, hydroxy, amine, nitro, C _1- C _{a 4-} alkylamino group (ie, -NH--C _1- C ₄ alkyl), a C _1- C ₄ dialkylamino group (ie, -N-[C _1- C ₄ alkyl] ₂ , wherein the alkane a phenyl group, a mono-, di- or tri-substituted phenyl group, wherein the substituent on the phenyl group is independently selected from a C ₁ -C ₈ alkyl group, C _{1 -} C ₈ alkoxy, fluorinated C _1- C ₈ alkyl, fluorinated C _1- C ₈ alkoxy, halogen, cyano, ethyl hydrazine, carboxyl, hydroxy, amine, nitro, alkylamine a dialkylamino group or a five or six membered heteroaryl group having from 1 to 3 heteroatoms selected from N, O and S.

The term "heteroaryl" as used herein denotes a stable unsubstituted or substituted five or six membered monocyclic or bicyclic aromatic ring system which consists of a carbon atom and one to three heteroatoms selected from N, O and S. composition. Heteroaryl groups can be attached at any heteroatom or carbon atom that results in a stable structure. Examples of heteroaryl groups include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl , benzotriazolyl, benzoxazolyl, furanyl, furfuryl, furyl, imidazolyl, oxazolyl, pyridazinyl, indanyl, fluorenyl, Isobenzofuranyl, isodecyl, isothiazolyl, isoxazolyl, oxazolyl, indolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoline Quinolinyl, quinolyl, thiadiazolyl, thiazolyl, thiophenyl or triazolyl. When the heteroaryl group is substituted, the heteroaryl group may have 1 to 3 substituents including, but not limited to, a C ₁ -C ₈ alkyl group, a halogen, and an aryl group.

The term "heterocyclyl" embraces optionally substituted non-aromatic rings having a carbon atom and at least one heteroatom (O, S, N) or a heteroatom moiety (SO ₂ , CO, CONH, COO) in the ring. Heterocyclyl groups can be saturated, partially saturated, non-aromatic or fused. Examples of the heterocyclic group include a cyclohexylimine group, an imidazolidinyl group, an imidazolinyl group, a morpholinyl group, a hexahydropyrazinyl group, a hexahydropyridyl group, a pyridyl group, a pyranyl group, a pyrazolyl group, a pyrazoline. Base, pyrrolidinyl, pyrrolinyl and thienyl.

Unless otherwise stated, heteroaryl and heterocyclyl can have via a carbon atom (eg, 3-furyl or 2-imidazolyl), or via a heteroatom (eg, N-hexahydropyridyl or 1-pyrazolyl) The valence that links it to the rest of the molecule. Preferably, the monocyclic heterocyclic group has 5 to 7 ring atoms, or 5 to 6 ring atoms; 1 to 5 hetero atoms or hetero atom portions may be present in the ring, and preferably 1 to 3, or 1 Up to 2 heteroatoms or heteroatoms.

Heterocyclyl and heteroaryl also include fused (e.g., bicyclic) rings, such as, as the case may be, optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring fused. For example, "heteroaryl" embraces optionally substituted hexa-aryl, which contains 1, 2 or 3 nitrogen atoms and is fused to an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. A heterocyclic ring. The heterocyclic five- or six-membered aromatic ring fused via the five- or six-membered aromatic ring may contain 1, 2 or 3 nitrogen atoms (wherein a six-membered ring), or 1, 2 Or 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur (wherein a five-membered ring).

The definition of any substituent or variable at a particular position in a molecule is intended to be independent of the definition of that molecule elsewhere. It will be appreciated that those skilled in the art will be able to select substituents and substitution patterns on the compounds of the invention to provide compounds which are chemically stable and which can be readily synthesized by the techniques of the art and by the methods described herein.

When the chemical moieties in, for example, ethoxymethyl or phenylethyl are combined, the term is described in terms of the point of attachment from the periphery of the molecule to the rest of the molecule. For example, ethoxymethyl based CH ₃ CH ₂ OCH ₂ - and phenylethyl line by --CH ₂ CH ₂ - and the remainder of the molecule of phenyl (the phenyl group and not by a a CH ₃ CH ₂ group of a substituent attached to the phenyl group of the molecule). When parentheses are used, they represent peripheral substitutions.

I. Introduction

The present invention is based, in part, on the surprising discovery that the PPAR δ agonists of the invention are effective in reducing the amount of dense small LDL particles in human blood. Note that almost all patients treated with this compound showed significantly improved LDL particle distribution. In fact, in the initial study, after treatment with a dose of 100 or 200 mg, each patient treated with the compound had an LDL subclass A pattern (ie, a peak LDL particle size greater than 263.4). ), and before treatment, the patient is A, I (between 263.4 and 257.5) Between) and B (less than 257.5 ) Mixed mode of mode. In addition, both LDL-cholesterol and lipoprotein B-100 levels were reduced in patients treated with the compound, while HDL levels were increased. In view of this data, it has been found that the compounds of the invention are particularly beneficial for individuals having smaller major LDL particle sizes (e.g., B or I mode).

II . The compound of the present invention

As described herein, the use of PPAR δ agonists allows the method of reducing the number of human dense small LDL particles, as well as reducing lipoprotein B-100, LDL-cholesterol and triglyceride levels, increasing HDL-cholesterol content and inhibition. Method of cholesterol synthesis and absorption. Various PPAR delta agonists are known in the art and include, but are not limited to, those disclosed below.

Compounds which are known to be selective PPARδ are well known in the art and comprise, for example, a compound known as GW501516 (for example as described in WO 01/00603) and a compound known as L-165,041 (for example, as in Europe) Patent Application No. 28063 and WO 97/28149).

In addition to L-165016 and GW501516, a variety of compounds which are agonists and have relatively high activity for subtype PPAR8 are disclosed, for example, in WO2002100351, WO0200250048, WO0179197, WO0246154, WO0214291, and Japanese Patent Application No. 2001-354671. In addition, Brown P J et al. reported compounds such as GW2433 (Brown P J, et al, Chem. Biol. 909-918 (1997)).

It is to be understood that additional PPAR δ agonists can be determined by screening methods, including, but not limited to, those described in U.S. Patent Publication No. 20070037882 and the references cited therein.

In certain embodiments, the invention features a PPAR δ agonist having a compound of formula (I) below:

Wherein X is selected from a covalent bond, S or O; Y is S or O; and W---- is selected from the group consisting of ==CH-, -CH==, -CH ₂ -, -CH ₂ - a group of CH ₂ , ==CH-CH ₂ , -CH ₂ CH==, ==CH-CH== and -CH==CH-; the Z system is selected from O, CH and CH ₂ , and the constraints are When Y is O, Z is O; R ₁ and R _{2 are} independently selected from H, C _1-3 alkyl, C _1-3 alkoxy, halo and NR _a R _b , wherein R _a and R _{b are} independently Is H or C _1-3 alkyl; R ₃ and R _{4 are} independently selected from H, halo, cyano, hydroxy, ethyl hydrazino, C _1-5 alkyl, C _1-4 alkoxy and NR _c R _d , wherein R _c and R _{d are} independently H or C _1-3 alkyl, the restriction is that both R ₃ and R ₄ are not H; R ₅ is selected from halo, phenyl, phenoxy, (phenyl)C _1-5 alkoxy, (phenyl) C _1-5 alkyl, C _2-5 heteroaryloxy, C _2-5 heteroaryl C _1-5 alkoxy, C _{2 -5heterocyclyloxy} , C _1-9 alkyl, C _1-8 alkoxy, C _2-9 alkenyl, C _2-9 alkenyloxy, C _2-9 alkynyl, C _2-9 Alkynyloxy, C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkyl-C _1-7 alkyl, C _3-7 cycloalkyl-C _1-7 alkane group, C _3-7 cycloalkyl -C _1-6 alkyl group, C _1-6 alkoxy -C _1-6 alkyl, C _1-5 alkoxy -C _1-5 alkoxy Group, a C _3-7 cycloalkyl group, or -C _1-7 alkoxy group; when --- --- W is a group selected from _{-CH ==, - CH 2, -CH} 2 -CH 2, -CH _{When 2} -CH== and -CH==CH-, R ₆ is H; or when --W--- represents ==CH-, ==CH-CH ₂ and ==CH-CH= When a group of =, R ₆ is absent; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.

Examples of a plurality of exemplary compounds within the scope of Formula I and the synthetic routes used to produce such compounds are described in, for example, U.S. Patent No. 7,301,050, the disclosure of which is incorporated herein by reference. For example, the invention encompasses each of the compounds disclosed in Table 1 of U.S. Patent No. 7,301,050.

In certain embodiments, the compound used in the method of the invention is a compound of formula II:

Or a salt, prodrug or isomer thereof. In certain embodiments, the compound is Or a salt, prodrug or isomer thereof.

When a compound of the invention has at least one pair of palmitic centers, it can therefore exist in enantiomeric form. When a compound has two or more pairs of palmitic centers, it may additionally exist as a diastereomeric form. It is to be understood that all such equivalents and mixtures thereof are encompassed within the scope of the invention. Moreover, certain crystalline forms of the compounds may exist in polymorphic forms and are likewise intended to be included in the present invention. In addition, certain compounds may form solvates with water (i.e., hydrates) or with common organic solvents, and such solvates are also intended to be encompassed within the scope of the invention.

The present invention provides a closely related pharmaceutically acceptable form of the disclosed compounds and the disclosed compounds, for example, a salt, an ester, a guanamine, a hydrate or a solvated form thereof; a masked or protected form; and a racemic mixture, or Enantiomer or optically pure form.

Pharmaceutically acceptable salts, esters, and guanamines include carboxylate (eg, C _1-8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic) amino acid addition salts, Esters and guanamines are pharmacologically effective at reasonable benefit/risk ratios and are suitable for contact with the tissue of a patient without undue toxicity, irritation or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate , borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, Glucose, lactobate and lauryl sulfonate. These may include alkali metal and alkaline earth metal cations (eg, sodium, potassium, calcium, and magnesium) as well as non-toxic ammonium, quaternary ammonium, and amine cations (eg, tetramethylammonium, methylamine, trimethylamine, and ethylamine). . See, for example, SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66: 119, which is incorporated herein by reference. Representative pharmaceutically acceptable guanamines of the invention include those derived from ammonia, a primary C _1-6 alkylamine, and a secondary di(C _1-6 alkyl)amine. The secondary amine comprises a 5- or 6-membered heterocyclic or heteroaromatic ring moiety containing at least one nitrogen atom and optionally 1 to 2 additional heteroatoms. Preferred guanamines are those derived from ammonia, C _1-3 alkyl primary amines and di(C _1-2 alkyl) amines. Representative pharmaceutically acceptable esters of the invention comprise a C _1-7 alkyl group, a C _5-7 cycloalkyl group, a phenyl group, and a phenyl (C _1-6 ) alkyl ester. In certain embodiments, the esters are methyl esters.

The invention also encompasses the disclosed compounds having one or more functional groups (e.g., amine or carboxyl groups) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; some will serve as intermediates. Synthetic intermediates and processes (e.g., as disclosed in U.S. Patent No. 7,301,050) and minor modifications thereof are also within the scope of the invention.

Hydroxy protecting group

The protection for the hydroxy group comprises methyl ether, substituted methyl ether, substituted diethyl ether, substituted benzyl ether and methyl decyl ether.

Substituted methyl ether

Examples of substituted methyl ethers include methyloxymethyl, methylthiomethyl, tert-butylthiomethyl, (phenyldimethylformamidinyl)methoxymethyl, benzyloxymethyl , p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacol methyl, tert-butoxymethyl, 4-pentenyloxymethyl , formazanoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethyl) Ethylmethyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyran , 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxo bridge, 1-[(2-chloro-4-methyl)phenyl] 4-methoxyhexahydropyridin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a,4,5,6,7 , 7a-octahydro-7,8,8-trimethyl-4,7-methylenebenzofuran-2-yl.

Substituted ether

Examples of the substituted diethyl ether include 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyl Oxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylformamidinylethyl, 2-(phenyl Hydrogen selenide) ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl.

Substituted benzyl ether

Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-di Chlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-pyridylmethyl, 3-methyl-2-pyridylmethyl N-oxy bridge, diphenylmethyl, p,p '-Dinitrodiphenylmethyl, 5-dibenzocycloheptyl, triphenylmethyl, α.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di P-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromobenzylidenemethyloxy)phenyldiphenylmethyl, 4,4 ',4"-叁(4,5-dichlorobenzimidazolylphenyl)methyl, 4,4',4"-fluorene (levulinoyloxyphenyl)methyl, 4,4',4"-叁(benzylideneoxyphenyl)methyl, 3-(imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl 1,1-bis(4-methoxyphenyl)-1'-fluorenylmethyl, 9-fluorenyl, 9-(9-phenyl)xanthene, 9-(9-phenyl-10 - pendant oxy) fluorenyl, 1,3-benzodithiolan-2-yl and benzisothiazolyl S, S-dioxo bridge.

Formamyl ether

Examples of the mercapto alkyl ether include trimethylcarbinyl, triethylcarbyl, triisopropylcarbyl, dimethylisopropylformamidin, diethylisopropylformamidin, and Methylhexylmethyl decyl, tert-butyldimethylformamidin, tert-butyldiphenylformamidinyl, tribenzylcarbylalkyl, tris-p-xylylmethylmercaptoalkyl, triphenylmethyl a decyl group, a diphenylmethyl formamyl group, and a third butyl methoxy phenyl methoxyalkyl group.

ester

In addition to the ether, the hydroxyl group can be protected as an ester. Examples of esters include formates, benzalkonate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, Triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-phenyl acetate, 3-phenylpropionate, 4-oxo valeric acid Ester (acetammonium propionate), 4,4-(ethylidene dithio) valerate, pivalate, adamantate, crotonate, 4-methoxy crotonate, benzoic acid Ester, p-phenyl benzoate, 2,4,6-trimethyl benzoate (vegetate).

Carbonate

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylmethylindenyl)ethyl, 2-(phenylsulfonyl) Ethyl, 2-(triphenylphosphino)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxy Base benzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl and methyl dithiocarbonate.

Auxiliary dissociation

Examples of auxiliary dissociation include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2- Mercaptobenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate and 2-(methylthiomethoxymethyl)benzene Formate.

Hybrid ester

Examples of the hybrid ester include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxy Acetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2 -methyl-2-butenoate (tigloate), o-(methoxycarbonyl)benzoate, p-benzoate, alpha-naphthoate, nitrate , N, N, N', N'-tetramethylphosphonium diammonium alkyl ester, N-phenyl urethane, borate, dimethylphosphinyl and 2,4-dinitro Phenyl sulfenyl ester.

Sulfonate

Examples of the sulfonate include a sulfate, a methanesulfonate, a mesylate, a benzyl sulfonate, and a tosylate.

Amine protecting group

The protection for the amine group comprises a urethane, a guanamine and a proprietary -NH protecting group.

Examples of urethanes include methyl carbamate and ethyl carbamate, substituted ethyl carbamate, co-dissociated urethane, photolyzed urethane, urea Derivatives and hybrid urethanes.

Urethane

Examples of methyl carbamate and ethyl carbamate include methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)nonylmethyl, 9-(2,7-di Bromo) decylmethyl, 2,7-di-t-butyl-[9-(10,10-di- oxo-10,10,10,10-tetrahydrothioxyl)] And 4-methoxybenzimidylmethyl.

Substituted ethyl

Examples of substituted ethyl carbamate include 2,2,2-trichloroethyl, 2-trimethylformamidinylethyl, 2-phenylethyl, 1-(1-adamantyl) 1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2, 2,2-trichloroethyl, 1-methyl-1-(4-biphenyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and 41-pyridyl)ethyl, 2-(N,N-dicyclohexylcarbinyl)ethyl, tert-butyl, 1-adamantyl, vinyl, allyl , 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolinyl, N-hydroxyhexahydropyridyl, alkyldithio, benzyl, p-methoxybenzyl, p-Nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-fluorenylmethyl and diphenylmethyl.

Auxiliary dissociation

Examples of auxiliary dissociation include 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithiaalkyl)]- Base, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphinoethyl, 2-triphenylphosphinoisopropyl, 1,1-dimethyl-2-cyanide Ethyl ethyl, m-chloro-p-nonyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzoisoxazolylmethyl and 2-(trifluoromethyl)-6-chromone Methyl group.

Photodissociation

Examples of photodissociation include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl and phenyl (o-nitro Phenyl) methyl.

Urea derivative

Examples of the urea-type derivative include a phenothiazine-(10)-carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl, and N'-phenylaminothiocarbonyl.

Hybrid urethane

Examples of the mixed urethane include a third pentyl group, a S-benzyl thiocarbamate, a p-cyanobenzyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, a cyclopropylmethyl group, and a fluorene group. Benzyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylformamido)benzyl, 1,1-dimethyl 3-(N,N-dimethylformamido)propyl, 1,1-dimethylpropynyl, bis(2-pyridyl)methyl, 2-furylmethyl, 2-iodo Ethyl, isodecyl, isobutyl, isoheptinyl, p-(p'-methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1- Methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-(p-phenylazophenyl)B , 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6- Tri-t-butylphenyl, 4-(trimethylammonium)benzyl and 2,4,6-trimethylbenzyl.

Examples of indoleamines include:

Guanamine

N-methyl fluorenyl, N-ethyl fluorenyl, N-chloroethyl fluorenyl, N-trichloroethyl fluorenyl, N-trifluoroethyl fluorenyl, N-phenylethyl fluorenyl, N-3-phenyl propyl Mercapto, N-pyridinecarboxylidene, N-3-pyridylcarbamamine, N-benzimidylphenylamine oxime derivative, N-benzylidene, N-p-phenylbenzamide base.

Auxiliary dissociation

N-o-nitrophenylethyl fluorenyl, N-o-nitrophenoxyethyl fluorenyl, N-acetyl fluorenyl, (N'-dithiobenzyloxycarbonylamino) ethyl fluorenyl, N-3-(p-hydroxyphenyl)propanyl, N-3-(o-nitrophenyl)propanyl, N-2-methyl-2-(o-nitrophenoxy)propenyl, N-2-methyl-2-(o-phenylazo phenoxy)propanyl, N-4-chlorobutylidene, N-3-methyl-3-nitrobutylidene, N-o-nitrocin , N-ethyl methionine derivative, N-o-nitrobenzylidene, N-o-(benzylideneoxymethyl)benzylidene and 4,5-diphenyl -3-oxazolin-2-one.

Cyclic quinone imine derivatives

N-o-phthalimide, N-dithiosuccinyl, N-2,3-diphenylmaleyl, N-2,5-dimethylpyrrolyl, N-1,1, 4,4-Tetramethyldimethyl sulfonyl azacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5 - substituted 1,3-dibenzyl-1,3,5-triazacyclo-2-one and 1-substituted 3,5-dinitro-4-pyridinone.

Proprietary-NH protecting group

Examples of proprietary NH protecting groups include:

N-alkyl and N-arylamine

N-methyl, N-allyl, N-[2-(trimethylcarbinyl)ethoxy]methyl, N-3-ethoxypropyloxy, N-(1-isopropyl 4-nitro-2-oxo-3-pyrroline-3-yl), quaternary ammonium salt, N-benzyl, N-bis(4-methoxyphenyl)methyl, N-5 -dibenzocycloheptyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylindenyl, N-2,7-dichloro -9-decyl methylene, N-ferrocenylmethyl and N-2-pyridylmethylamino N'-oxide.

Imine derivative

N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)trimethylbenzene Methylene and N-(N',N'-dimethylaminomethylene).

For the protection of carboxyl groups

ester

Examples of esters include formates, benzalkonate, acetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, p-chlorophenoxy Base acetate, benzoate.

Substituted methyl ester

Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(three Methyl methoxyalkyl) ethoxymethyl, benzyloxymethyl, benzamidine methyl, p-bromobenzylidenemethyl, .α.-methylbenzimidylmethyl, p-methoxybenzene Formamidine methyl, formamidine methyl and N-xamethylene iminomethyl.

2-substituted ethyl ester

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl, 2-haloethyl, (.Ω.-chloroalkyl, 2-(trimethylformamidinyl)ethyl , 2-methylthioethyl, 1,3-dithiaalkyl-2-methyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(p-toluenesulfonyl)ethyl , 2-(2'-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, tert-butyl, cyclopentyl, cyclohexyl, alkene Propyl, 3-buten-1-yl, 4-(trimethylcarbinyl)-2-buten-1-yl, cinnamyl, .α.-methylcinnamyl, phenyl, p-( Methyl fluorenyl) phenyl and benzyl.

Substituted benzyl ester

Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-fluorenylmethyl, 2-(9,10-di-oxyl) ) mercaptomethyl, 5-dibenzocycloheptyl, 1-decylmethyl, 2-(trifluoromethyl)-6-chromanylmethyl, 2,4,6-trimethylbenzyl , p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4 - sulfobenzyl, piperonyl, 4-pyridylmethyl and p-benzyl.

Mercaptoalkyl ester

Examples of the mercaptoalkyl ester include trimethylmethanyl, triethylcarbenyl, tert-butyldimethylformamidin, isopropyldimethylformamidin, phenyldimethylformamidin And di-t-butylmethylformamidinyl.

Activated ester

Examples of activated esters include thiols.

Hybrid derivative

Examples of hybrid derivatives include oxazole, 2-alkyl-1,3-oxazoline, 4-alkyl-5-o-oxy-1,3-oxazolidine, 5-alkyl-4-oxo Base-1,3-dioxolane, orthoester, phenyl and pentaaminocobalt (III) complex.

Stannyl ester

Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.

A method for the synthesis of a compound of formula I is previously described, for example, in U.S. Patent No. 7,301,050.

III. Patient population

As evidenced by the data provided herein, certain classes of individuals can derive particularly significant benefits from the acceptance of PPAR δ agonists, such as those described in Formula I and as described herein. Those who receive particularly significant benefits include those individuals with smaller major LDL particles (eg, B or I mode), those with high lipoprotein B-100 blood levels, and/or those with high triglycerides And / or cholesterol. As shown by the data presented herein, it has surprisingly been surprisingly found that the compounds of the invention are effective in solving each of the risk factors listed above, ie by significantly reducing the amount of smaller LDL particles, lowering lipoprotein B -100, blood levels of LDL cholesterol and triglycerides, elevated blood levels of HDL cholesterol, and by blocking both cholesterol synthesis and absorption.

Thus, in certain embodiments, a compound of the invention is administered to an individual having a B-mode or an I-mode primary LDL particle size. In certain embodiments, a compound of the invention (eg, a compound of Formula II) is administered to an individual having a primary LDL particle size of less than 26.34 nm (as measured by GGE) and a primary LDL particle size within the individual Depending on the situation, it becomes larger than 26.34 nm (as measured by GGE). In certain embodiments, a compound of the invention (eg, a compound of Formula II) is administered to an individual having a primary LDL particle size of less than 25.75 nm (as measured by GGE) and a primary LDL particle size within the individual Depending on the situation, it becomes larger than 25.75 nm and depending on the case, it is larger than 26.34 nm (as measured by GGE).

In certain embodiments, a compound of the invention (eg, a compound of Formula II) is administered to an individual having a primary LDL particle size of less than 212.0 nm (as measured by AIM) and a primary LDL particle size within the individual Depending on the situation, it becomes larger than 212.0 nm (as measured by AIM). In certain embodiments, a compound of the invention (eg, a compound of Formula II) is administered to an individual having a primary LDL particle size of less than 208.8 nm (as measured by AIM) and a primary LDL particle size within the individual Depending on the situation, it becomes larger than 208.8 nm and depending on the case, it is larger than 212.0 nm (as measured by AIM).

In certain embodiments, a compound of the invention (eg, a compound of Formula II) is administered to an individual having primary LDL-III particles (as measured by AIM). In certain embodiments, a compound of the invention (eg, a compound of Formula II) is administered to an individual having primary LDL-IV particles (as measured by AIM).

In certain embodiments, a compound of the invention is administered to an individual having a lipoprotein B-100 content (eg, blood content) of at least 130 mg/dl, such as at least 150 mg/dl or 175 mg/dl, optionally as appropriate Has an LDL particle size B or I mode. In certain embodiments, a compound of the invention is administered to an individual having a lipoprotein B-100 content of at least 130 mg/dl, in an amount and at a frequency sufficient to provide a lipoprotein B-100 content over a period of time (eg, 10, 20, 40, 70, 100 or more days), for example, from 130 mg/dl or more to 130 mg/dl or less and/or maintaining the desired target lipoprotein B-100 content at, for example, 130 mg/dl or less, 120 mg /dl or less, 100mg/dl or less.

In certain embodiments, a compound of the invention is administered to an individual having a non-HDL cholesterol content (eg, blood content) of at least 130 mg/dL, such as at least 150 mg/dL, optionally having an LDL particle size B or I. mode. In certain embodiments, a compound of the invention is administered to an individual having a non-HDL cholesterol content of at least 130 mg/dL in an amount and frequency sufficient to provide a non-HDL cholesterol content over a period of time (eg, 10, 20, 40, 70, 100 or more days) is reduced from, for example, 130 mg/dL or more to 130 mg/dL or less and/or the desired target non-HDL cholesterol content is maintained below, for example, 130 mg/dL.

In certain embodiments, a compound of the invention is administered to an individual having an LDL-cholesterol content (eg, a fasting blood cholesterol level) of at least 130 mg/dL, such as at least 150 mg/dL, optionally having an LDL particle size B Or I mode. In certain embodiments, a compound of the invention is administered to an individual having a cholesterol content of at least 130 mg/dL in an amount and frequency sufficient to provide cholesterol levels over a period of time (eg, 10, 20, 40, 70, 100 or more) Days (for example) are reduced from above 130 mg/dL to below 110 mg/dL and/or to maintain the desired target cholesterol content below, for example, 110 mg/dL.

In certain embodiments, a compound of the invention is administered to an individual having metabolic syndrome, optionally also having an LDL particle size B or I pattern. Metabolic syndrome is characterized by a population of metabolic risk factors in a human body. It contains: (a) abdominal obesity (too much abdomen and surrounding adipose tissue); (b) atherogenic dyslipidemia (lipidemia - high triglycerides, low HDL cholesterol and high LDL cholesterol - Fuchs) (foster spots accumulate in the arterial wall); (c) elevated blood pressure; (d) insulin resistance or glucose intolerance (the body is unable to properly utilize insulin or blood glucose); (e) prethrombotic state (eg, High fibrinogen or plasminogen activator inhibitor-1) in the blood; and (f) pro-inflammatory state (eg, high C-reactive protein in the blood)

In certain embodiments, a compound of the invention is administered to an individual having diabetes or having insulin resistance, optionally having an LDL particle size B or I mode, and/or a non-HDL cholesterol content greater than or equal to 130 mg/dL.

In certain embodiments, a compound of the invention is administered to an individual having atherosclerosis, optionally also having an LDL particle size B or I pattern. In certain embodiments, a compound of the invention is administered to an individual who does not have atherosclerosis but optionally has an LDL particle size B or I pattern.

In certain embodiments, the individual (eg, human) LDL particle size, lipoprotein B-100 content, LDL cholesterol content, triglyceride are tested prior to, during, and/or after administration of a compound of the invention. Ester content, insulin resistance and/or glucose tolerance. Such tests are used, for example, to initially determine the individual from which the compounds will benefit the most, as well as to monitor therapeutic efficacy and, where appropriate, to determine treatments that may be ameliorated by modification or replacement therapy. Thus, in certain embodiments, the treatment of the individual is altered after determining LDL particle size, lipoprotein B-100 content, LDL cholesterol content, triglyceride content, insulin resistance, and/or glucose tolerance.

Measurements of lipoprotein B-100, LDL cholesterol, triglyceride content, LDL particle size, or blood levels of other blood factors are typically determined from blood samples from fasted individuals.

Two exemplary methods for determining the size of LDL particles include gradient gel electrophoresis (GGE) and airborne ion transport (AIM) methods. It is believed that although both methods produce substantially the same results, there is still a difference between the two methods to some extent, and unless otherwise stated, AIM is used to determine the LDL particle size. GGE is described in Krauss and Burke, J Lipid Res. 23:97-104 (1982) and La Belle et al, J. Lipid Res. 38 690-700 (1997). AIM is described in Caulfield et al, Clin. Chem. 54: 1307-1316 (2008).

IV. Formulations and Administration

According to the present invention, a therapeutically effective amount of a PPAR δ agonist (e.g., a compound of formula I) can be used to reduce, for example, the amount of smaller LDL particles, reduce the blood content of lipoprotein B-100, lower the blood content of LDL cholesterol, and lower glycerol. Triglyceride content, elevated HDL cholesterol content and/or reduced cholesterol synthesis and/or absorption, as described herein.

The compositions of the present invention may comprise a compound of formula (I), a pharmaceutically acceptable salt thereof or a hydrolyzable precursor thereof. In certain embodiments, the compound is combined in a therapeutically effective amount with a suitable carrier or excipient.

The compounds of formula (I) used in the methods of the invention can be incorporated into a variety of formulations for therapeutic administration. More specifically, a PPAR δ agonist comprising a compound of formula (I) can be formulated into a pharmaceutical composition by combining with a suitable pharmaceutically acceptable carrier or diluent, and can be formulated as a solid, semi-solid, Formulations in liquid or gaseous form, such as tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalants, and aerosols. Thus, administration of the compound can be accomplished in a variety of ways, including orally, buccally, rectally, parenterally, intraperitoneally, intradermally, transdermally, intratracheally. In addition, the compounds can be administered in the form of a storage or sustained release formulation. Alternatively, the compound can be administered in the form of a liposome.

The compound of formula (I) can be formulated with conventional excipients, diluents or carriers and compressed into troches or formulated into elixirs or solutions for convenient oral administration or administration by intramuscular or intravenous routes. The compounds can be administered transdermally and can be formulated into sustained release dosage forms and the like. The compounds of formula (I) may be administered alone or in combination with each other or they may be used in combination with other conventional compounds.

Suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences (Mace Publishing Company (1985), Philadelphia, Pa., 17th Edition), which is incorporated herein by reference. Further, for a review of methods of drug delivery, see Langer Science (1990) 249: 1527-1533, which is incorporated herein by reference. The pharmaceutical compositions described herein can be made by conventional methods known to those skilled in the art, i.e., by conventional mixing, dissolving, granulating, pelletizing, grinding into a powder, emulsifying, encapsulating, embedding or lyophilizing process. To manufacture. The following methods and excipients are illustrative only and are in no way limiting.

For injection, the compound can be dissolved, suspended or emulsified in an aqueous or non-aqueous solvent (eg vegetable oil or other similar oil, synthetic fatty acid glyceride, higher fatty acid or propylene glycol ester); and (if needed) Conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives are formulated together. In certain embodiments, the compounds of the invention may be formulated in aqueous solutions, for example, in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, a penetrant suitable for the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds of formula (I) can be readily formulated by combination with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds to be formulated into lozenges, pills, dragees, capsules, emulsions, lipophilic and hydrophilic suspensions, liquids, gels, syrups, slurries, suspensions, and And so on. Pharmaceutical preparations for oral use can be obtained by mixing the compound with a solid excipient, grinding the resulting mixture as appropriate, and processing the mixture of granules after adding suitable auxiliaries, if necessary, to obtain a lozenge or dragee core. Suitable excipients are especially fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl fiber , hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP). If necessary, a disintegrating agent such as crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (for example, sodium alginate) may be added.

A suitable coating is provided for the dragee core. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions. And a suitable organic solvent or solvent mixture. Dyestuffs or pigments may also be added to the tablets or dragee coatings to identify or characterize different combinations of active compound agents.

Pharmaceutical preparations which can be used orally include a co-insertion capsule made of gelatin, and a soft-sealed capsule made of gelatin and a plasticizer such as glycerol or sorbitol. The co-injection capsules may contain the active ingredient in admixture with admixtures (such as lactose), binders (such as starch) and/or lubricants (such as talc or magnesium stearate) and, if appropriate, stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer may be added. All formulations administered orally should be in dosages suitable for this administration.

For buccal administration, the compositions may take the form of lozenges or lozenges formulated in a conventional manner.

For administration by inhalation, the compounds used in the present invention may be prepared by the use of a suitable propellant (for example, dichlorodifluoromethane, trichlorofluoroethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). It is conveniently delivered as an aerosol spray by a pressure device or nebulizer or by a dry powder inhaler without propellant. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. For example, gelatin capsules and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compound can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection can be provided in unit dosage form, for example, in ampoules or in multi-dose containers, with the addition of a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain such compositions as suspensions, stabilizers and/or dispersing agents.

Pharmaceutical formulations for parenteral administration comprise an aqueous solution of the active compound in water soluble form. Alternatively, suspensions of the active compounds can be prepared in a suitable oily injection suspension. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain materials which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compound to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle (for example, sterile, pyrogen-free water) prior to use.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas containing, for example, conventional suppository bases such as cocoa butter, carbowax, polyethylene glycol or other glycerides, all of which melt at body temperature while Cured at room temperature.

In addition to the above formulations, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymeric or hydrophobic material (for example, as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative (for example, formulated as a sparingly soluble salt) .

Alternatively, other types of delivery for hydrophobic pharmaceutical compounds can be used. Well-known examples of delivery vehicles or carriers for hydrophobic drugs are liposomes and emulsions. In the presently preferred embodiment, longer cycles, i.e., stealth liposomes, can be used. Such liposomes are outlined in U.S. Patent No. 5,013,556 to Woodle et al. The compounds of the present invention can also be administered by controlled release methods and/or delivery devices, such as those described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, and 4,008,719.

Certain organic solvents (such as dimethyl hydrazine (DMSO)) can also be used, but usually at the expense of increased toxicity. Additionally, the compound can be delivered by sustained release, such as a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic agent. A variety of sustained release materials have been identified and are well known to those skilled in the art. Sustained-release capsules can release compounds for up to 100 days depending on their chemical nature.

The pharmaceutical compositions may also include suitable solid phase or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

Pharmaceutical compositions suitable for use in the present invention comprise a composition wherein the active ingredient is contained in a therapeutically effective amount. Of course, the amount of the composition administered will depend on the individual being treated, the weight of the individual, the severity of the pain, the mode of administration, and the judgment of the prescribing physician. Determination of an effective amount is well known within the skill of those skilled in the art, especially in light of the detailed disclosure provided herein.

For any of the compounds used in the methods of the invention, a therapeutically effective dose can be estimated initially from cell culture assays or animal models.

Moreover, toxicity and therapeutic efficacy described herein may be a compound of by standard pharmaceutical procedures in cell cultures or experimental animals measured, e.g., (50% of the population dose death) and by measuring ED ₅₀ LD ₅₀ (the population 50% of the therapeutically effective dose) is determined. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio of LD ₅₀ to ED ₅₀ of. Compounds that exhibit high therapeutic indices are generally preferred. Data obtained from such cell culture assays and animal studies can be used to tune the dose range for non-toxicity in humans. Dosage of such compounds preferably having low or no toxicity within a range of circulating concentrations (containing ED _50). The dosage may vary within this range depending on the dosage form employed and the route of administration employed. Each physician can select the exact formulation, route of administration, and dosage based on the condition of the patient. (See, for example, Fingl et al., 1975, The Pharmacological Basis of Therapeutics, Chapter 1).

The amount of active compound which may be combined with the carrier materials to produce a single dosage form will vary depending upon the condition being treated, the type of mammal, and the particular mode of administration. Exemplary dosages will of course depend on the compound employed. As a general guide, suitable unit doses of the compounds of the invention may contain, for example, from 10 mg to about 3000 mg of the active compound, for example, a unit dose of between 50 mg to about 1500 mg, for example, a unit dose of between 50 and Between about 500 mg. 50, 100 and 200 mg doses as disclosed in the examples Effective for improving patient (eg) LDL particle size.

Unit doses (eg, as discussed above) may be administered more than once a day, for example 1, 2, 3, 4, 5 or 6 times a day, but as appropriate 1 or 2 times a day for 70 kg The total daily dose for an adult is in the range of 0.1 to about 250 mg/kg of patient weight/injection. An exemplary dosage is from 5 to about 250 mg/kg of patient weight/administration and the treatment may be extended for weeks or months and in some cases for several years. However, it should be understood that the particular dosage amount used for any particular patient will depend on a number of factors, including the activity of the particular compound employed; the age, weight, overall health, sex, and diet of the individual to be treated; time and route of administration The rate of excretion; other drugs previously administered; and the severity of the particular disease being treated, should be well known to those skilled in the art.

A typical dose may be a 10 to about 1500 mg lozenge, taken once a day or multiple times a day; or a delayed release capsule or lozenge, taken once a day, and containing a higher proportion of active ingredient . In certain embodiments, a dose of 10, 25, 50, 100, 200 or 300 milligrams is provided per day. The delayed release effect can be obtained by a capsule material that dissolves at different pH values, a capsule that is slowly released by osmotic pressure, or by any other conventional controlled release means.

In some cases it may be necessary to use dosages in excess of those ranges, as will be apparent to those skilled in the art. In addition, it should be noted that the clinician or treating physician should know how and when to combine the patient responses to interrupt, modulate or terminate the treatment.

The compounds of the invention may be used in combination with other pharmaceutically active agents.

Methods for determining the effective dosage of a disclosed pharmaceutical composition or combination of disclosed drugs, whether or not formulated into the same composition, are well known in the art for therapeutic and prophylactic purposes. For therapeutic purposes, the term "combination effective amount" as used herein means to cause a tissue system, animal or human to elicit each active compound or agent alone or in combination with the biological or medical response being sought by a researcher, veterinarian, physician or other clinician. An amount comprising a symptom that alleviates the disease or condition being treated. For the purpose of prevention (ie, inhibition of the onset or progression of a condition), the term "combinationally effective amount" means a combination or combination, as the investigator, veterinarian, physician or other clinician is seeking to treat or inhibit the onset or progression of the condition of the individual. The amount of each active compound or agent. Thus, the invention provides a combination of two or more drugs, wherein, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination is sub- Therapeutic or sub-prophylaxis (if administered alone) is administered, and when administered in combination with a second or additional drug of the invention, is therapeutic or prophylactic; or (c) two (or more) drugs are Sub-therapeutic or sub-prophylaxis (if administered alone) is administered, but when administered together, it is therapeutic or prophylactic.

Antidiabetic agents include thiazolidinedione and non-thiazolidinedione insulin sensitizers (which reduce peripheral insulin resistance by enhancing the action of insulin at target organs and tissues), and sulfonylureas (eg, Glyburide), biguanides (eg metformin), DPP-4 inhibitors (eg, sitagliptin), incretin analogs (eg, exenatide) ), meglitinide (eg, Nateglinide), and an alpha-glucosidase inhibitor (eg, acarbose).

It is known that some of the following agents bind to and activate the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ), which increases the transcription of specific insulin-responsive genes. Examples of PPAR-gamma agonists are thiazolidinediones, for example: (1) rosiglitazone (2,4-thiazolidinone, 5-((4-(2-(methyl-2-)) Pyridylamino)ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1:1) or 5-((4-(2-(methyl-2-pyridine) yl amino) ethoxy) phenyl) methyl) piperidine-2,4-thiazol-dione, known as AVANDIA ^TM; also known as BRL 49653, BRL 49653C, BRL 49653c , SB 210232, or rosiglitazone MA (2) pioglitazone (2,4-thiazolidinone, 5-((4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)) ,), monohydrochloride, (+-)- or 5-((4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)methyl)-2,4- thiazol-piperidin-dione, known as ACTOS ^TM, ZACTOS ^TM, or GLUSTIN ^TM; also known as AD 4833, U 72107, U 72107A , U 72107E, pioglitazone hydrochloride ^{(USAN TM)); (3} ) troglitazone ( Troglitazone)(5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy) ) phenyl) methyl) piperidine-2,4-thiazol-dione, known as ^{NOSCAL TM, REZULIN TM, ROMOZIN TM} , or PRELAY ^TM; also referred to as C1 991, CS 045, GR 92132 , GR 92132x) (4) Saglitazone ((+)-5-[[6-[(2-fluorophenyl)methoxy]-2-naphthyl]methyl]-2,4-thiazolidine II Ketone or 5-((6-((2-fluorophenyl)methoxy)-2-naphthyl)methyl-2,4-thiazolidinone or 5-(6-(2-fluorobenzyloxy) (naphthalen-2-ylmethyl)thiazolidin-2,4-dione, also known as MCC-555 or neoglitazone); and (5) 5-BTZD.

Further, the non-thiazolidinedione used as the insulin sensitizer includes, but is not limited to: (1) JT-501 (JTT 501, PNU-1827, PNU-716-MET-0096, or PNU 182716: isoxazole) Pyridine-3,5-dione, 4-((4-(2-phenyl-5-methyl)-1,3-oxazolyl)ethylphenyl-4)methyl-); (2) KRP-297(5-(2,4-dioxaoxythiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl)benzyl)benzamide or 5 -((2,4-di-oxy-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide ); and (3) Farglitazar (L-tyrosine, N-(2-benzhydrylphenyl)-O-(2-(5-methyl-2-phenyl-) 4-oxazolyl)ethyl)- or N-(2-benzhydrylphenyl)-O-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)- L-tyrosine, or GW2570 or GI-262570).

Other agents have also been shown to have PPAR modulator activity, such as PPAR gamma, SPPAR gamma, and/or PPAR delta/gamma agonist activity. Examples are listed below: (1) AD 5075; (2) R 119702 ((+-)-5-(4-(5-methoxy-1H-benzimidazol-2-ylmethoxy)benzyl) Thiazoline-2,4-dione hydrochloride, or C1 1037 or CS 011); (3) CLX-0940 (peroxisome proliferator-activated receptor alpha agonist / peroxisome proliferator Activated receptor gamma agonist); (4) LR-90 (2,5,5-indole (4-chlorophenyl)-1,3-dioxane-2-carboxylic acid, PPARδ/γ agonist); 5) Tularik (PPAR gamma agonist); (6) CLX-0921 (PPAR gamma agonist); (7) CGP-52608 (PPAR agonist); (8) GW-409890 (PPAR agonist); (9) GW- 7845 (PPAR agonist); (10) L-764406 (PPAR agonist); (11) LG-101280 (PPAR agonist); (12) LM-4156 (PPAR agonist); (13) lesatstat ( Risarestat) (CT-112); (14) YM 440 (PPAR agonist); (15) AR-H049020 (PPAR agonist); (16) GW 0072 (4-(4-((2S,5S)-5) -(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazolidinyl)butyl)benzoic acid); 17) GW 409544 (GW-544 or GW-409544); (18) NN 2344 (DRF 2593); (19) NN 622 (DRF 2725); (20) AR-H039242 (AZ-242); (21) GW 9820 (Bate); (22) GW 1929 (N-(2- Benzomethylene phenyl)-O-(2-(methyl-2-pyridylamino)ethyl)-L-tyrosine, known as GW 2331, PPAR α/γ agonist); (23) SB 219994((S)-4-(2-(2-benzoxazolylmethylamino)ethoxy)-α-(2,2,2-trifluoro-ethoxy)benzenepropionic acid or 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2(S)-(2,2,2-trifluoro Ethoxy)propionic acid or phenylpropionic acid, 4-(2-(2-benzoxazolylmethylamino)ethoxy)-α-(2,2,2-trifluoroethoxy)- , (αS)-, PPAR α/γ agonist); (24) L-796449 (PPAR α/γ agonist); (25) Fenofibrate (propionic acid, 2-[4-(4) - chlorobenzamide acyl) phenoxy] -2-methyl -, 1-methylethyl ester, known as ^{TRICOR TM, LIPCOR TM, LIPANTIL TM} , LIPIDIL TM MICRO PPAR α agonist); (26) GW -9578 (PPAR alpha agonist); (27) GW-2433 (PPAR alpha/gamma agonist); (28) GW-0207 (PPAR gamma agonist); (29) LG-100641 (PPAR gamma agonist); (30) LY-300512 (PPAR gamma agonist); (31) NID525-209 (NID-525); (32) VDO-52 (VDO-52); (33) LG 100754 (peroxisome proliferator Activated receptor agonist); (34) LY-510929 (peroxisome proliferator activity) Receptor agonist); (35) bexarotene (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalene) yl) ethenyl) benzoic acid, known as ^{TARGRETIN TM, TARGRETYN TM, TARGREXIN TM} ; also known as LGD 1069, LG 100069, LG 1069 , LDG 1069, LG 69, RO 264455); and (36) GW-1536 (PPAR Alpha/gamma agonist).

In certain embodiments, the PPAR δ agonist of the invention is a compound having one of the formula:

Or a pharmaceutically acceptable salt or solvate combination thereof. The compound of the above formula may be a racemic isomer, a (+) isomer or a (-) isomer. A method for the preparation of such compounds is taught in U.S. Patent Application Publication No. 20030220399, the disclosure of which is incorporated herein by reference. A method of analysing an alpha-(phenoxy)phenylacetic acid derivative is taught in U.S. Patent Application Publication No. 20050033, the entire disclosure of which is incorporated herein by reference.

(B) Other insulin sensitizers include (but are not limited to): (1) INS-1 (D-chiral inositol or D-1,2,3,4,5,6-hexahydroxycyclohexane); (2) protein tyrosine phosphatase 1 B (PTP-1B) inhibitor; (3) glycogen synthase kinase-3 (GSK3) inhibitor; (4) β 3 adrenergic receptor agonist, such as ZD 2079 ((R)-N-(2-(4-(carboxymethyl)phenoxy)ethyl)-N-(2-hydroxy-2-phenylethyl)ammonium chloride, also known as ICI D 2079) Or AZ 40140; (5) glycogen phosphorylase inhibitor; (6) fructose-1,6-bisphosphatase inhibitor; (7) chromium picolinate, vanadyl sulfate (vanadium oxysulfate); KP 102 (organic-vanadium compound); (9) chromium polynicotinate; (10) potassium channel agonist NN 414; (11) YM 268 (5,5'-methylene-bis(1,4-stretch) Phenyl) bismethylene bis(thiazolidine-2,4-dione)); (12) TS 971; (13) T 174 ((+-)-5-(2,4-di-side oxythiazole) Pyridin-5-ylmethyl)-2-(2-naphthylmethyl)benzoxazole-); (14) SDZ PGU 693 ((+)-trans-2(S-((4-chlorophenoxy) Methyl)-7α-(3,4-dichlorophenyl)tetrahydropyrrolo(2,1-b)oxazole-5(6H)-one); (15) S 15261((-)- 4-(2-((9H-茀-9-ylethyl)amino)ethyl)benzoic acid 2-((2-methoxy-2-() 3-(trifluoromethyl)phenyl)ethyl)amino)ethyl ester); (16) AZM 134 (Alizyme); (17) ARIAD; (18) R 102380; (19) PNU 140975 (1- (nonylimidomethyl)mercapto)acetic acid; (20) PNU 106817 (2-(decamimidinomethyl)indolyl)acetic acid; (21) NC 2100 (5-((7-(benzene) Methoxy)-3-quinolinyl)methyl)-2,4-thiazolidinone; (22) MXC 3255; (23) MBX 102; (24) ALT 4037; (25) AM 454; 26) JTP 20993 (2-(4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)benzyl)-malonic acid dimethyl diester); (27 ) Dexlipotam (5(R)-(1,2-dithiolan-3-yl)pentanoic acid, also known as (R)-alpha-acid or (R)-lipoic acid) (28) BM 170744 (2,2-dichloro-12-(p-chlorophenyl)dodecanoic acid); (29) BM 152054 (5-(4-(2-(5-methyl-2-) (2-thienyl)oxazol-4-yl)ethoxy)benzothiophen-7-ylmethyl)thiazolidin-2,4-dione); (30) BM 131258 (5-(4-( 2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)benzothiophen-7-ylmethyl)thiazolidin-2,4-dione); (31) CRE 16336 ( EML 16336); (32) HQL 975(3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2(S)-(C Amino) propionic acid); (33) DRF 2 189 (5-((4-(2-(1-indolyl)ethoxy)phenyl)methyl)thiazolidine-2,4-dione); (34) DRF 554158; (35) DRF- NPCC; (36) CLX 0100, CLX 0101, CLX 0900, or CLX 0901; (37) IkappaB kinase (IKK B) inhibitor; (38) mitogen-activated protein kinase (MAPK) inhibitor p38 MAPK stimulator; (39) phospholipid creatinine triphosphate; (40) insulin recirculation receptor inhibitor; (41) glucose transporter 4 modulator; (42) TNF-α antagonist; (43) plasma cell differentiation antigen-1 (PC-1) antagonist; (44) adipocyte lipid-binding protein (ALBP/aP2) inhibitor; (45) phosphopolysaccharide; (46) galparan; (47) Receptron (48) islet cell maturation factor; (49) insulin potentiating factor (IPF or insulin potentiating factor-1); (50) growth regulator C binding to binding protein (also known as IGF-BP3, IGF-BP3, SomatoKine) (51) Diab II (called V-411) or Glucanin, manufactured by Biotech Holdings Ltd. or Volque Pharmaceutical; (52) Glucose-6 phosphatase inhibitor; (53) Fatty acid glucose transporter Protein; (54 a glucocorticoid receptor antagonist; and (55) glutamine amide: a 6-phosphate-fructose thiotransferase (GFAT) modulator.

(C) Biguanides, which reduce hepatic glucose production and increase glucose uptake. Examples include metformin such as: (1) 1,1-dimethyl biguanide (e.g., Metformin-DepoMed, Metformin-Biovail Corporation; or METFORMIN ^TM GR (metformin gastric retention polymer)); and (2) metformin hydrochloride (N, N- dimethyl-acyl imine carbon iminodiacetic acid monohydrochloride Amides (N, N-dimethylimidodicarbonimidic diamide monohydrochloride ), also known as LA 6023, BMS 207150, GLUCOPHAGE ^TM or GLUCOPHAGE XR ^TM.

(D) an alpha-glucosidase inhibitor that inhibits alpha-glucosidase. Alpha-glucosidase converts fructose into glucose, thereby delaying the digestion of carbohydrates. Undigested carbohydrates then break down in the intestine, reducing postprandial glucose peaks. Examples include, but are not limited to: (1) acarbose (D-glucose, O-4,6-dideoxy-4-(((1S-(1α,4α,5β,6α)))-4) ,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)amino)-α-D-glucopyranosyl-(1-4)-O-α-D - glucopyranosyl - (1-4) -, also known as AG-5421, Bay-g- 542, BAY-g-542, GLUCOBAY TM, PRECOSE TM, GLUCOR TM, PRANDASE TM, GLUMIDA TM, or ASCAROSE ^TM (2) Miglitol (3,4,5-hexahydropyridinol, 1-(2-hydroxyethyl)-2-(hydroxymethyl)-, (2R(2α,3β) , 4α, 5β))- or (2R, 3R, 4R, 5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl-3,4,5-hexahydropyridinol, also known as BAY 1099, BAY m 1099, BAY -m-1099, BAYGLITOL TM, DIASTABOL TM, GLYSET TM, MIGLIBAY TM, METOLBAY TM, PLUMAROL TM); (3) CKD-711 (0-4- go-4- ( (2,3-epoxy-3-hydroxymethyl-4,5,6-trihydroxycyclohexane-1-yl-)amino)-α-b-glucopyranosyl-(1-4)- α-D-glucopyranosyl (1-4)-D-glucopyranose); (4) emiglitate (4-(2-R(3R, 3R, 4R, 5S)-3, Ethyl 4,5-trihydroxy-2-(hydroxymethyl)-1-hexahydropyridyl)ethoxy)benzoate Also known as BAY o 1248 or MKC 542); (5) MOR 14 (3,4,5-hexahydropyridinol, 2-(hydroxymethyl)-1-methyl-, (2R-(2α,3β) , 4α, 5β))-, also known as N-methyldeoxynojirimycin (N-methyldeoxynojirimycin) or N-methylmoranoline (N-methylmoranoline); 6) Voglibose (3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl))amino)-2-C-(hydroxymethyl) )-D-table-inositol or D-table-inositol, 3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C - (hydroxymethyl) -, also known as ^{A 71100, AO 128, BASEN TM} , GLUSTAT TM, VOGLISTAT TM).

(E) Insulin contains timed or short-acting, medium- and long-acting insulin, non-injected or inhaled insulin, tissue-selective insulin, glucophosphokinin (D-chiro inositol), insulin analogues (eg Insulin molecules and small molecule insulin mimetics (insulin mimics) and endosomal modulators that differ slightly from the native amino acid sequence. Examples include (but are not limited to): (1) Biota; (2) LP 100; (3) (SP-5-21)-sideoxy bis(1-pyrrolidinedithiocarbamic acid vanadium-S, S '), (4) insulin aspart (human insulin (28B-L-aspartate) or B28-Asp-insulin, also known as insulin X14, INA-X14, NOVORAPID ^TM , NOVOMIX ^TM or NOVOLOG ^TM ); 5) Detemir (human 29B-(N-6-(1-sided oxytetradecyl)-L-lysine)-(1A-21A), (1B-29B)-insulin or NN 304) (6) insulin lispro ("28B-L-lysine-29B-L-proline human insulin" or Lys (B28), Pro (B29) human insulin analog, also known as lys-pro insulin, ^{LY 275585, HUMALOG TM, HUMALOG TM} MIX 75/25 , or ^{HUMALOG TM MIX 50/50); (7} ) insulin glargine (human (A21- glycine, B31- arginine, B32- arginine) insulin HOE 901, also known as ^{LANTUS TM, OPTISULIN TM); (} 8) insulin zinc suspension, long-acting (Ultralente), also known as HUMULIN ^TM U or ULTRALENTE ^TM; (9) insulin zinc suspension (Lente), 70% crystalline and 30% amorphous insulin suspension, also known as LENTE ILETIN ^TM II, HUMULIN ^TM L, or ^{NOVOLIN TM L; (10) HUMULIN} TM 50 / 50 (50% isophane insulin and 50% insulin ^{injection); (11) HUMULIN TM 70/30} (70% isophane insulin NPH and 30% insulin injection), also known as NOVOLIN ^TM 70/30, NOVOLIN ^{TM 70/30 PenFill, NOVOLIN TM 70/30 Prefilled;} (12) insulin isophane suspension such ^{NPHILETIN TM II, NOVOLIN TM N,} NOVOLIN TM N PenFill, NOVOLIN TM N Prefilled, HUMULIN TM N; (13) regular insulin injection, e.g. ^{ILETIN TM II Regular, NOVOLIN TM R} , VELOSULIN TM BR, NOVOLIN TM R PenFill, NOVOLIN TM R Prefilled, HUMULIN TM R , or Regular U-500 ^{(concentrated); (14) ARIAD TM;} (15) LY 197535 ;(16) L-783281; and (17) TE-17411.

(F) Insulin secretion regulators, for example: (1) Glucagon-like peptide-1 (GLP-1) and its mimetic; (2) Glucose-insulinotropic peptide (GIP) and its mimetic; (3) Love Exendin and its mimetic; (4) dipeptidyl protease (DPP or DPPIV) inhibitors, such as (4a) DPP-728 or LAF 237 (2-pyrrolidine carbonitrile, 1-(((2- ((5-Cyano-2-pyridyl)amino)ethyl)amino)ethinyl), known as NVP-DPP-728, DPP-728A, LAF-237); (4b) P3298 or P32/ 98 (bis-(3N-((2S,3S)-2-amino-3-methyl-pentanyl)-1,3-thiazolidine) fumarate); (4c) TSL 225 (tryptamine Mercapto-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid); (4d) pyrrolidine (valpyr); (4e) 1-aminoalkylisoquinolinone-4- Formate and its analogues; (4f) SDZ, 272 070 (1-(L-Amidinoindolyl) pyrrolidine); (4g) TMC-2A, TMC-2B or TMC-2C; (4h) dipeptide Nitrile (2-cyanopyrrolidine); (4i) CD26 inhibitor; and (4j) SDZ 274-444; (5) glucagon antagonists, such as AY-279955; and (6) amylin agonists, It includes, but is not limited to, pramlintide (AC-137, lymphline acetate (Symlin), trisamine-dextrin ( Tripro-amylin) or pramlintide acetate).

The compounds of the invention may also increase insulin sensitivity and have little or no increase in body weight compared to the use of existing PPAR gamma agonists. Oral antidiabetic agents can include insulin, sulfonylurea, biguanide, meglitin, AGI agonists, PPAR alpha agonists, and PPAR gamma agonists, and dual PPAR alpha/gamma agonists.

The compounds of the invention may also increase fat and/or lipid metabolism, providing a means of reducing body weight, reducing fat weight, reducing body mass index, lowering lipids (e.g., lowering triglycerides), or treating obesity or overweight conditions. Examples of the lipid lowering agent include a bile acid sequestrant, a fibric acid derivative, a nicotinic acid, and an HMGCoA reductase inhibitor. Specific examples include such as ^{LIPITOR TM, ZOCOR TM, PRAVACHOL TM} , LESCOL TM and MEVACOR ^TM and other disabilities statins, and pitavastatin (pitavastatin) (nisvastatin (nisvastatin) (Nissan, Kowa Kogyo , Sankyo, Novartis) and extended release Forms (eg ADX-159 (extended release lovastatin)), as well as Colestid, Locholest, Questran, Atromid, Norfolk (Lopid) and Tricor.

Examples of blood pressure lowering agents include antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors (Accupril, ALTAMI, Captopril, Lotensin). Lotensin, Mavik, Monopril, Prinovil, Univasc, Vasotec, and Jasper Zestril)), adrenergic blockers (eg Cardura, Dibenzyline, Hylorel, Hytrin, Minipress, and Hydrochloride) Amizidine-polythiazide (Minizide), α/β-adrenergic blockers (eg, Coreg, Normodyne, and Trandate), calcium channel blockers (eg, Adalat, Calan, Cardene, Cardizem, Covera-HS, Dilacor, DynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia, Nifedipine XL, Sula, Nitroza Tiazac), Vascor and Vernin (V Erelan)), diuretics, angiotensin 11 receptor antagonists (eg, atacand, Avapro, Cozaar, and Diovan), beta adrenaline Blockers (eg Betapace, Blocadren, Brevibloc, Cartrol, Inderal, Karl) Kerlone), Lavatol, Lopressor, Sectral, Tenormin, Toprol-XL and Zebeta ), vasodilators (such as Deponit, Dilatrate, SR, Imdur, Ismo, Isordil, Love Speed Scratch ( Isordil Titradose), Monoket, Nitro-Bid, Nitro-Dur, Nitrolingual Spray, Nitrostat and Sorebitrate )), and combinations thereof (eg Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzide) , Uniretic, Vaughan (Vaseretic), Zestoretic.

In certain embodiments, the methods of the invention comprise administering a compound of the invention for a prolonged period of time.

Instance Example 1: Compound II affects the concentration of LDL particle subclasses

High plasma concentrations of low density lipoprotein (LDL) increase the risk of cardiovascular disease. In addition, as measured by airborne ion mobility, the lipid profiles involved in densely packed small LDL particles (subclass B mode) involve a greater risk than they are mainly from larger floatable LDL particles (subclass A mode). The composition is large. It has been demonstrated that the compound of formula II, the PPAR δ activator, effectively increases the size of the primary LDL particle, in part by reducing the amount of smaller LDL particles.

Thirty-six healthy male individuals were treated with 50, 100 and 200 mg of the compound of formula II for 21 days. The lipoprotein particle size of the individual was determined before and after administration of the compound using gradient gel electrophoresis (GGE) and airborne ion mobility (AIM) methods.

GGE is implemented essentially as described in Krauss and Burke, J Lipid Res. 23:97-104 (1982) and La Belle et al, J. Lipid Res. 38 690-700 (1997) by non-denaturing 2- The LDL particle size was determined by 14% polyacrylamide gradient gel electrophoresis in 0.09 M Tris/0.08 M borate buffer (pH 8.3), 3 mM EDTA at 8-10 °C. Samples (entire plasma) were electrophoresed for 15 minutes at 40 V, followed by electrophoresis at 80 V for 15 minutes, and then electrophoresed at 125 V for 24 hours to allow all particles to run to their size exclusion limits. The protein gel was stained with Sudan black and scanned with a Transidyne RFT hydrometer at 555 nm. High molecular weight reference protein mixture (Pharmacia Biotech., Piscataway, NJ), 380 Latex beads (Duke Scientific, Palo Alto, CA) and lipoprotein calibrators (which were frozen at -80 ° C and included in each gel experiment) were calculated from the calibration curve for particle size. Plasma samples stored at -80 ° C and used as controls for the gradient gel analysis procedure were run in duplicate on each gel. The LDL peak particle size in these controls was measured at ±2 Internal (offset coefficient, ±1%).

AIM is generally implemented as follows, as described in Caulfield et al., Clin. Chem. 54: 1307-1316 (2008):

test Sample preparation:

Mix serum samples or controls by vortex mixing, then 5 μl of sample or control with 20 μl of albumin removal reagent [7.5 g/L of active green 19 glucan (RGD), Sigma-Aldrich; 2.5 g/L dextran sulfate, Sigma-Aldrich; and 0.5 g/L EDTA, Spectrum Chemicals] were mixed and incubated on ice for 15 minutes. After incubation, the sample mixture was overlaid onto 200 microliters of cerium oxide (medical isotope) in a 42.2 ultracentrifuge tube (Beckman Coulter). The sample was ultracentrifuged at 223,000 g (42,000 rpm) for 135 minutes at 10 °C, and then the upper 85 microliter sample (ie, lipid fraction) was removed. Samples were diluted 1:800 at 25:8 mM/L ammonium acetate, 0.5 mmol/L ammonium hydroxide pH 7.4 for HDL analysis. For LDL analysis, the sample was diluted 1:200 with the same diluent containing 5 μg/ml dextran sulfate to help prevent adhesion of LDL particles to the capillary surface. The final dilution was performed in a deep well 96-well plate and placed in a Leap HTLC Pal autosampler (Eksigent) with the cooling jacket maintained at 6 °C.

Lipoprotein analysis:

The autosampler was coupled to an electrospray generator (model 3480; TSI) via a methyl-deactivated ceria capillary (50 microliter id; SGE). A stream of mobile phase introducing 25 millimoles per liter of ammonium acetate, 0.5 millimoles per liter of ammonium hydroxide pH 7.4 was run by nano-LC pumping (Eksigent). An autosampler was used to inject 10 microliters of the sample into the transfer capillary (methyl-deactivated, SGE, 50 micron, 33 cm long) at 6 microliters per minute by means of a capillary metal combination (Upchurch Scientific). A high voltage (2.1 kV) was applied to the metal capillary assembly, which was located 33 cm upstream of the electrospray unit. The electrospray Taylor cone was monitored by visual and galvanic analysis to ensure stability. After the sample was filled with the capillary and reached the electrospray chamber, the flow rate was reduced to 200 nL/min and the data recording process was initiated. The gas flowing into the electrospray chamber (containing about 5% CO ₂ ) was adjusted to 1.6 L/min. Electrospray particles pass through the particle-charge neutralization chamber and then enter a differential mobility analyzer (DMA). See, for example, U.S. Patent No. 7,259,018. Scan time is 2 minutes and covers 17.2 to 542.0 The range of particles. After the scan is completed, the data corresponding to the specific range of the particles of the lipoprotein subclass is collected by totaling particles passing through a predetermined 0.1-s band (corresponding to a specific subclass), and the main LDL particle size is determined (the mode) diameter).

in conclusion

Lipid analysis of multiple incremental dose (MAD) samples of stage I showed that MBX-8025 significantly reduced LDL-cholesterol and lipoprotein B (Figure 1).

To further understand the mechanism of action of the compound of formula II ("Compound II"), plasma samples obtained before treatment (Day 1) and after treatment (Day 21) were analyzed to determine LDL particles by gradient gel electrophoresis. size. Specify LDL subclass A, B or I mode for each individual sample based on the peak diameter size of the LDL particles (A mode: >263.4 , I mode: 257.5-263.4 , B mode: <257.5 ).

An inverse relationship between plasma triglyceride concentration and peak (i.e., major) LDL diameter was observed in the 21 day sample. As shown in Figures 2, 3 and 4, Compound II treatment increased the primary LDL particle size at doses of 50, 100, and 200 mg, reducing the proportion of smaller LDL particles and thus the primary LDL particle size from LDL B or I. The mode changes to LDL A mode. Compound II did not affect the VLDL particle size, but affected the LDL particle distribution in a dose-dependent manner. Figure 5 illustrates the effect of Compound II on LDL particle subclasses after 21 days.

A second clinical study was performed to determine the effect of the compound of formula II on the size of LDL particles in an overweight individual. In this study, individuals met the following criteria: no diabetes; no treatment or diet, and fasting lipids during initial screening and the second visit (after 4 weeks of running): but ; but ; . Women with a waist circumference greater than 38" or women with a waist circumference greater than 33". Data were generated from 181 individuals in this second study.

Table I shows the number of individuals with the specified LDL pattern before or after the indicated time period after the start of treatment. For example, in the placebo group, at the beginning of the study, 10 individuals had an LDL A pattern, 3 individuals had an LDL I pattern and 16 individuals had an LDL B pattern. After 8 weeks of placebo, only 6 individuals had an LDL A pattern and 13 individuals had an LDL B pattern. Among the 28 individuals retained in the placebo cohort study, there was a net decrease in individuals with the LDL A pattern. In comparison, in the group treated with 50 mg of Compound II, the number of individuals with smaller atherogenic A mode increased from 8 to 24 and 25, respectively, at 4 and 8 weeks of treatment, and The number with the B mode drops similarly. Treatment with 100 mg of Compound II had similar results, and individuals with a B-mode decreased significantly and the number of individuals with A-mode increased. These results were superior to the control group treated with statin and atorvastatin (LIPITOR).

The above data is also summarized in Figures 7-8. Figure 7 shows that the percentage of individuals with LDL A mode decreased over time when treated with placebo, but increased significantly when administered Compound II. Figure 8 shows that the percentage of individuals with LDL B mode increased with time when treated with placebo, but decreased significantly when Compound II was administered.

The results of various blood chemistry markers from this study are shown in Figure 6. Among them, the data showed that Apo B-100, LDL, total cholesterol and triglycerides decreased after administration of Compound II, and HDL content increased. The results of this observation were interesting because atorvastatin had no effect on HDL levels. These data indicate that Compound II is particularly beneficial for individuals who need or otherwise benefit from increased HDL levels.

Example 2: Compound II affects cholesterol synthesis

A series of experiments were performed to determine the effect of Compound II on cholesterol synthesis. Compound II was administered to human subjects and the effect on cholesterol ester, thiol-CoA: cholesterol thiotransferase (ACAT) and lecithin-cholesterol thiotransferase (LACAT) was determined after 21 days. This treatment reduces the cholesterol concentration in a dose dependent manner. It appears that the therapeutic effect between ACAT- and LCAT-derived cholesteryl esters is similar, indicating a decrease in cholesterol quality.

As shown in Figure 9, lanosterol, dehydrocholesterol, and 7-enylcholol were all major cholesterol synthesis intermediates and all decreased in a dose-dependent manner, indicating a decrease in cholesterol synthesis using treatment.

Example 3: Compound II affects cholesterol absorption

This study was designed to examine the effect of Compound II on intestinal cholesterol absorption in mice using the double isotope ratio method of feces. Male C57BL/6 mice, 8 weeks old, were fed ad libitum to a standard mouse mixed diet (control) without the addition of cholesterol (Harlan Teklad diet T.8604). The mice were randomly divided into five groups: 1) control, daily feeding by water; 2) daily feeding to compound II (in water) at a dose of 3 mg/kg; 3) daily at a dose of 10 mg/kg Feeding to compound II (in water); 4) daily feeding to Ezetimibe (in corn oil) at a dose of 5 mg/kg; 5) feeding daily at a dose of about 15 mg/kg Compound II as a dietary mixture. Mice were individually housed and food consumption and body weight were monitored daily. 8 days after feeding/drug administration (and 1 hour after tube feeding), blood was drawn from unfasted, unanesthetized animals and plasma was separated and rapidly frozen at -80 °C for shipment and measurement of Compound II and The concentration of metabolites. The next day (Day 9), the tube was fed a mouse drug or control. One hour later, the tube was fed to each mouse with MCT oil containing [ ¹⁴ C]cholesterol and [ ³ H]dihydrositosterol. Mice were individually housed in metabolic cages and allowed to eat freely and each tube was fed daily for gavage. Feces were collected from each animal every day for 4 days. For each individual mouse, 4 days of feces were collected, dried, saponified, extracted and counted.

Intestinal cholesterol absorption in age- and sex-matched C57BL/6 mice was determined by the fecal double isotope ratio method. C57BL/6 control mice were found to have absorbed 33.9% [ ^14C ] cholesterol. See Figure 10. Treatment with Compound II by gavage at a dose of 3 mg/kg/day did not produce a significant change (-8%) in terms of cholesterol absorption compared to the control. In contrast, treatment with Compound II by gavage at a dose of 10 mg/kg/day significantly reduced cholesterol absorption by 29.4% compared to the control. Compound II treatment at a dose of about 15 mg/kg/day as a dietary mixture even reduced more in cholesterol absorption than in the control (-45%, p < 0.0006). This change was not significantly different from the 10 mg/kg/day dose. As a positive control, ezetimibe at a dose of 5 mg/kg/day resulted in a significant reduction in cholesterol absorption of 56.4% (p < 0.0000005). Statistical analysis between groups was evaluated by unpaired Student's t-test. Statistical significance is defined as a two-tailed rate of less than 0.05.

In another experiment, human subjects received an oral dose of Compound II daily on Day 1 and thereafter and evaluated the effect of the drug on Day 21. Phytosterols are poorly absorbed from the diet but are absorbed in proportion to dietary cholesterol and are therefore useful as good cholesterol absorption markers. As shown in Figure 11, β-sitosterol and canola sterol were significantly reduced in a dose-dependent manner, indicating a decrease in cholesterol absorption by treatment. Stigmasterol is clearly unaffected by treatment.

It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or variations are apparent to those skilled in the art and are intended to be Within the scope of the scope. The entire disclosures of all publications, patents, and patent applications cited herein are hereby incorporated by reference herein in their entirety

Figure 1 illustrates the effect of a compound of formula II on LDL-cholesterol and lipoprotein B-100;

Figure 2 illustrates the effect of Compound II on LDL patterns after 21 days of treatment;

Figure 3 illustrates the change in the distribution of LDL particles with the dose of Compound II (determined by AIM);

Figure 4 illustrates the effect of Compound II on peak LDL diameter after 21 days of treatment;

Figure 5 illustrates the effect of Compound II on LDL particle subclasses after 21 days;

Figure 6 summarizes the effect of Compound II as described in the Examples on individual blood components in obese individuals;

Figure 7 illustrates the percentage of patients with LDL A mode after various treatment regimens;

Figure 8 illustrates the percentage of patients with LDL B or I mode after various treatment regimens;

Figure 9 illustrates the amount of lanosterol, dehydrocholesterol and 7-encholyl alcohol (all cholesterol intermediates) in the blood of an individual after administration of Compound II;

Figure 10 illustrates the effect of Compound II on cholesterol absorption in mice after administration of Compound II;

Figure 11 illustrates the absorption of human phytosterols following administration of Compound II.

Claims (15)

a use of a compound of the formula or a salt thereof, It is used to manufacture a medicament for administration to a human having an LDL particle size B mode or an I mode to change the particle size mode from B mode to I mode or A mode, or from I mode to A mode, To treat diabetes, insulin resistance, atherosclerosis, metabolic syndrome or dyslipidemia, wherein the LDL particle size B mode is the main LDL particle size is less than 25.75 nm, and the I mode is the main LDL particle size of 25.75 nm to 26.34 The meters, and the A mode, have a major LDL particle size greater than 26.34 nm, which is measured by gradient gel electrophoresis. The use of claim 1, wherein the human has a lower content of LDL-III particles after administration, wherein the LDL-III particles are measured by airborne ion migration and have a diameter of 20.17 LDL particles up to 21.10 nm. The use of claim 1, wherein the human has a lower content of LDL-IV particles after administration, wherein the LDL-IV particles are measured by airborne ion migration and have a diameter of 18.00 LDL particles up to 20.17 nm. The use of claim 1, wherein the human has LDL particles after 10 days of administration Size A mode. The use of claim 1, wherein the human has an LDL particle size B mode prior to administration. The use of claim 1 wherein the human lipoprotein B-100 blood content is reduced by at least 10% after 10 days of administration. The use of claim 1, wherein the human cholesterol absorption is reduced by at least 5%, at least 10%, or at least 20% after 10 days of administration. The use of claim 1, wherein the human cholesterol synthesis is reduced by at least 5%, at least 10%, or at least 20% after 10 days of administration. The use of claim 1, wherein the human has diabetes. The use of claim 1, wherein the human is insulin resistant. The use of claim 1, wherein the human has atherosclerosis. The use of claim 1, wherein the human has a metabolic syndrome. The use of claim 1, wherein the human has dyslipidemia. The use of claim 1, wherein the agent is used in combination with statin. The use of claim 14, wherein the statin is atorvastatin.